Cystic fibrosis(CF) is the most common genetic disorder and the largest genetic killer of children. One in twenty Caucasians carries a defective CF gene, which, when coupled with a spouse who is also a carrier can result in offspring afflicted with CF. An autosomal, recessive disorder, one in 3,000 children born in the United States and Europe inherit CF. Children live for varying periods of time, but the average has been extended from a couple of years early in this century to a current life expectancy of 30 years. Over 70,000 patients have been identified with Cystic Fibrosis worldwide. This translates into over 30,000 individuals with the disease in the United States with another 30,000 who have been identified with the disorder in Europe. As current treatment strategies prolong the average lifespan, the number of CF patients is expected to rise. Patients with CF typically incur medical costs ranging from $15,000 to $55,000 annually. In addition, carriers of CF (about 5% of Caucasians) have a higher likelihood of suffering from sinusitis, a disease of the sinus passages characterized by recurrent infections.
CF is due to a genetic defect in a chloride-channel in mucus membranes that regulates the passage of chloride, sodium and water into mucous linings. This leads to unusually thick mucus, particularly in the lungs, which encourages the growth of bacteria and consequently repeated infections and inflammation.
In a majority of CF victims, the cystic fibrosis transmembrane regulator (CFTR), an epithelial chloride channel, is defective. In 70% of the cases this is due to a single point mutation at ΔF508. Thus, CF mucosal epithelial cells are incapable of transferring sufficient amounts of chloride ions to the outer membrane surface to draw enough water to adequately hydrate the mucous membranes. The inherited disease process of CF affects tissues of mucous membranes such as those lining throat, nasal, sinus, bronchial passages, lungs, gall bladder, sweat glands, pancreas and intestines.
The disease causes abnormally viscous mucous secretions that lead to chronic pulmonary disease, pancreatic insufficiency and intestinal obstructions, together with a host of lesser but potentially lethal problems, such as an excessive loss of electrolytes in hot environments. In the past, afflicted children often died as infants. Although surviving into their twenties and thirties with current treatments, CF patients are plagued with recurrent infections and require daily arduous routines to clear air passageways.
It is believed that agents that promote chloride secretion such as purinergic agonists and other agents that elevate intracellular calcium could be useful in increasing hydration of the airways, thus reducing mucous viscosity. However, it is known that nucleotides already present in the fluid lining the lungs should be sufficient to stimulate a rise in levels of intracellular calcium. Thus, it may also be necessary to inactivate pathways that limit chloride secretion, such as those mediated by inositol polyphosphate and phosphoinositide pathways described below.
It has recently been shown that certain inositol phosphate derivatives including D-myo-inositol 3,4,5,6-tetrakisphosphate (“Ins(3,4,5,6)P4”) (M. Vajanaphanich et al., Nature 371:711 (1994); J. M. Uribe et al., J. Biol. Chem. 271(43):26588 (1996); M. T. Rudolf et al., J. Med. Chem. 41 (19):3635-3644 (1998)), and sn-di-O-palmitoylD,L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis(acetoxymethyl)ester (C. Schultz et al., Membrane-permeant, Bioactivatable Derivatives of Inositol Polyphosphates and Phosphoinositides, in Phosphoinositides. Chemistry, Biochemistry and Biomedical Applications, K. S. Bruzik, Ed. Am. Chem. Soc., Symp. Ser., 718, 232-243 (1999)) inhibit calcium-mediated chloride secretion. D-myo-Inositol 1,4,5,6-tetrakisphosphate has been shown to inhibit a phosphatidylinositol PI-3 kinase (“PI-3 kinase”) signaling pathway in colonic epithelia (Eckmarn et al., Proc. Natl. Acad. Sci. USA 94:14456 (1997)). It has also recently been shown that 2,6-di-O-butyryl-myo-inositol 1,2,4,5-octakis(acetoxymethyl)ester increased the level of Ca2+ in PC12 cells (C. Schultz et al. (1998), supra). U.S. Pat. No. 5,693,521 to Tsien et al. discloses the use of D-2,3-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis(acetoxy-methyl)ester as a second messenger having enhanced cell permeability. International Publication No. WO 98/11901 by Traynor-Kaplan et al. describes various inositol phosphates with enhanced cell permeability that function as either agonists or antagonists of inositol polyphosphates. In addition, the synthesis of other inositol phosphates has been reported (S. Roemer et al., J. Chem. Soc.; Perkin Trans. 1, 1683 (1996); International Publication No. WO 96/40695 to Tsien et al.; International Publication No. WO 98/11901 to A. Traynor-Kaplan et al.; Rudolf, M. T. et al., Bioorg. & Med. Chem. Lett., 8:1857 (1998); Jiang, T. et al., J. Biol. Chem. 273:11017 (1998); Li, W., et al., Tetrahedron 53:12017 (1997)).
Inflammation also plays a role in cystic fibrosis and other disorders. Inflammation is the body's response to injury and has been defined as a localized protective response to destroy, dilute or sequester the injurious agent and/or injured tissue. Classic macroscopic signs include pain, heat, redness, swelling and loss of function. On a microscopic level there is a dilatation of blood vessels with accompanying increased permeability and blood flow, exudation of fluids and infiltration of leucocytes. These responses are triggered by the release from the vascular system of inflammatory response mediators (e.g., histamine, prostaglandins, and leukotrienes) to destroy any bacteria or other toxins in the injured area and remove necrotic tissue. If this inflammatory response is somehow inappropriately triggered, toxic substances (i.e., reactive oxygen species-free radicals) that are associated with the inflammatory response mediators can destroy healthy tissues. A number of diseases such as asthma, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and adult respiratory distress syndrome (ARDS) result from such a faulty inflammatory response. In addition, consequences of acute inflammation result in irreparable tissue damage following heart attacks and strokes. In these cases much of the tissue destruction is caused by caustic oxygen radicals and their byproducts. It is now recognized that excessive release of oxygen radicals can lead to an overproduction of “wound healing” reactions such as release of growth factors that induce overproliferation of connective tissue and extracellular matrix components that can result in fibrosis, sclerosis, adhesions and scarring. Current therapies for these conditions such as steroids are ameliorative and do not resolve the core problems and are generally immunosuppressive. In addition, the available medications lead to side effects that restrict their long-term use. Therefore, a need persists for safe and effective anti-inflammatory agents.
To the best of Applicants' knowledge, the novel inositol polyphosphate derivatives of the present invention and the use of inositol polyphosphate derivatives for treating cystic fibrosis have not been previously known.